Abstract Here we seek to assist the FDA in its evaluation of topical products by developing, evaluating and improving a framework of physiologically based absorption and pharmacokinetic models for dermal absorption in response to the FDA call: Physiologically Based Absorption and Pharmacokinetic Modeling and Simulation for Non-gastrointestinally Absorbed Drug Products in Humans (RFA-FD-14-012), focusing on dermal absorption. We describe a framework of three physiologically based pharmacokinetic models to assist in this evaluation: 1. An analytical solution based on a Laplace Transform solution 2. A compartmental approach 3. A 3D numerical analysis to precisely mimic the geometry of the stratum corneum and processes that occur when a product is applied to the skin eg evaporation of some excipients, penetration of active and some excipients into the skin and transfer to deeper tissue and the systemic circulation This work is then validated by parameter sensitivity analyses, a comparison with of predictions with actual data observations and some in house validation studies. The final stage is an evaluation of the models using data from 2 CROs and 2 studies FDA are presently supporting that involve in vitro membrane, in vitro skin penetration, in vitro stratum corneum assays, in vivo stratum corneum assays and dermal assays. A key outcome here, as well as an adequate description of the data, is a population description of intra and intersubject variability and likely covariances. Our key goal is to predict active concentrations at their sites of action and in the blood over time.